The present invention relates to a pharmaceutical composition with high stability and, more precisely, to a pharmaceutical composition comprising an HMG-CoA reductase inhibitor of which the stability varies depending on pH, especially (E)-3,5-dihydroxy-7-[4xe2x80x2-4xe2x80x3-fluorophenyl-2xe2x80x2-cyclopropyl-quinolin-3xe2x80x2-yl]-6-heptenoic acid, or its salt or ester.
It is known that 7-substituted-3,5-dihydroxy-6-heptenoic acids of a general formula: 
wherein R represents an organic group, have HMG-CoA reductase-inhibiting activity, and are useful as medicines for hyperlipemia and also as medicines for atherosclerosis (see U.S. Pat. Nos. 4,739,073, 5,001,255, 4,751,235, 4,804,679, EP-B-304,063).
However, these 7-substituted-3,5-dihydroxy-6-heptenoic acids are unstable at low pH, and require some particular means for formulating them into preparations. A means of formulating them along with an alkaline medium, such as calcium carbonate or sodium carbonate, into preparations with pH of 8 or higher (see U.S. Pat. No. 5,356,896), and a means of formulating them along with a basic agent, such as magnesium oxide or sodium hydroxide, into preparations with pH of 9 or higher (see EP-B-336,298) have been proposed.
(E)-3,5-dihydroxy-7-[4xe2x80x2-4 xe2x80x3-fluorophehyl-2 xe2x80x2-cyclopropyl-quinolin-3xe2x80x2-yl]-6-heptenoic acid (hereinafter this may be referred to as NK-104) to be represented by a structural formula: 
or its salt or ester is one of HMG-CoA reductase inhibitors that are represented by the above-mentioned general formula, and is known to be useful as a medicine for hyperlipemia and also as a medicine for atherosclerosis (see EP-B-304,063). NK-104 is also unstable at low pH, and many difficulties have been encountered in formulating it into preparations.
It has been reported that these HMG-CoA reductase inhibitors are formulated into preparations with pH 8 or higher, desirably pH 9 or higher, but unexpectedly, it has been found that NK-104 and its salts and esters are still unstable even within a high pH range.
Therefore, preparations comprising NK-104 or its salt or ester, if formulated in conventional manners, have low time-dependent stability, and are problematic in that their outward appearance changes with the lapse of time. Given the situation, the development of stable preparations comprising it is desired.
We the present inventors have variously studied in order to obtain stable pharmaceutical compositions comprising NK-104 and, as a result, have found unexpectedly that NK-104 is stable within a relatively low pH range. On the basis of this finding, we have completed the present invention.
Furthermore, we investigated decomposition products of NK-104 and fluvastatin in an aqueous solution of pH3. The decomposition product of NK-104 was found in small quantity and consisted only of the lactonized form of NK-104 (see FIG. 1). On the other hand, decomposition products of fluvastatin were found in relatively large quantities consisting of more than one type of products which are believed to include an optical isomer and a lactonized form of fluvastatin (see FIG. 2). These results showed that the decomposition pattern and stability of NK-104 and fluvastatin were different in the same pH.
In addition, we have further found that, if a basic substance is added to a pharmaceutical composition comprising NK-104 in such a manner that the aqueous solution or dispersion of the composition may have pH of from 6.8 to 8, the composition is stable.
An object of the present invention is to provide a pharmaceutical composition comprising NK-104, or its salt or ester, of which the aqueous solution or dispersion has pH of from 6.8 to less than 8, preferably has pH of from 6.8 to 7.8.
The active ingredient of the composition of the present invention is NK-104 to be represented by the above-mentioned structural formula. The configuration in this substance, NK-104 is not specifically defined herein. In addition, NK-104 may be in any form of its salts and esters. The salts include, for example, sodium salt, potassium salt and calcium salt. Preferred is calcium salt of NK-104.